Amebiasis is the third leading cause of death from parasitic infection worldwide, following malaria and schistosomiasis. Imidazoles, particularly metronidazole, are the single class of drugs used worldwide for treatment. Resistance to metronidazole is a growing concern in multiple protozoa, including Giardia, Trichomonas vaginalis, and E. histolytica. Therefore, the identification of new drugs is a priority. This proposed clinical trial is based on important findings from a U01 grant to identify new drug targets in Class B protozoa. By screening all FDA approved drugs against E. histolytica trophozoites, we found one drug, auranofin, an oral gold-containing compound approved in 1985 to treat rheumatoid arthritis, had an IC50 of 0.5 M, 10-fold lower than metronidazole (5.2 M). Oral auranofin was also effective in rodent models of amebic colitis and liver abscesses, leading to approval of Orphan Drug status for the treatment of amebiasis. We propose to test the hypothesis that oral auranofin has equivalent efficacy to metronidazole for the treatment of amebic colitis. Our proposed clinical trial is a Phase IIa, 3 parallel arm, randomized, double blin treatment study comparing an active control (metronidazole) to once or twice daily doses of auranofin for treatment of adults with acute amebic colitis. We will focus on patients > 18 years old with symptomatic diarrhea (> 2 loose stools for 24 hrs) with E. histolytica (by O&P exam + specific antigen, serology, or PCR testing). They will be randomized to standard metronidazole therapy (500 mg tid for 10d), low dose auranofin (3 mg daily for 10d), or high dose auranofin, 3 mg bid daily for 10 d). The primary end-point will be time to resolution of diarrhea (no loose stools for 24 hrs) with a secondary end-point of time to parasitologic response by microscopy and quantitative PCR. This proposed clinical trial using a re-profiled FDA drug could result in the first new drug and target for the treatment of amebiasis in 52 years. PUBLIC HEALTH RELEVANCE: Amebiasis is a major cause of morbidity and mortality worldwide with only one class of drugs available for treatment. We have identified an FDA-approved drug, auranofin, which is highly active against the parasite causing amebiasis. We now propose to plan a clinical trial to test its efficacy compared to current therapy, which could lead to the first new drug and drug target to treat this neglected disease in 52 years.